This project was undertaken as part of final-year engineering research project to determine the optimal process for water for injection (WFI) production in terms of water consumption, energy requirements, sustainability and overall cost.
Water for Injection (WFI) is a water quality standard defined by pharmacopeial groups worldwide. WFI is a sterile water used mostly in the pharmaceutical industry for the production of parenteral drugs such as vaccines and for cleaning.
The specifications for WFI is more stringent than purified water (another water standard commonly used in the pharmaceutical sector) in terms of conductivity, total organic carbon, endotoxin and microbial levels.
WFI has been traditionally produced by distillation, utilising multiple effect distillation (MED) or vapour compression (VC) distillation, in order to produce hot water for injection (HWFI).
Over the years, distillation-based processes have been considered as the gold standard for WFI generation, due to the high operating temperatures providing an extra layer of protection against biofilm formation (2;ISPE, 2019).
Membrane technology has been used for WFI for some time in the US and Japan as it was permitted by their national pharmacopoeia. In Europe, membrane technology was only permitted for 'highly purified water'.
As membrane technology is believed to be more sustainable, the European pharmacopoeia has accepted it as an alternative method of producing WFI.
This process utilises membranes, such as reverse osmosis (RO) and ultrafiltration (UF), producing ambient water for injection (AWFI) at 15ᵒC.
The European pharmacopoeia has only accepted membrane technology for the production of WFI since 2017, hence there is a knowledge gap regarding the efficiency of the system compared to the traditional distillation generation processes (2; ISPE, 2019).
From completing the literature review, it was found that little supporting evidence was available to showcase the potential benefits of a membrane process with definite analytical data.
In addition, VC distillation can also operate at lower temperatures compared to MED and as a result, VC can also be used to produce AWFI. There are many configurations that can be considered in designing a process for HWFI and AWFI production in order to meet the requirements of the end user.
On that basis, a simplified approach for both AWFI and HWFI generation was considered in this study with the objective of presenting a comparison between the three main systems (membrane based, VC and MED) under the evaluation process stated above.
Process route selection
The main available technologies for the production of AWFI are VC and membrane-based systems while MED and VC are utilised for HWFI production.
The pre-treatment requirement for each system remains relatively similar, with small variations in the process flow of unit operations as seen in figures 1-3. VC offers the ability to operate on a simplified pre-treatment step (typically softened, dechlorinated feedwater) whereas, MED requires a water equivalent to 'purified water' grade.
The requirements for storage and distribution loops in WFI production are dependant on the temperature of the WFI being generated. For AWFI systems, an additional UV light unit is required for sanitation purposes in order to prevent the formation of biofilm. HWFI systems do not require additional sanitation as the high temperature makes the system self-sanitising (2; ISPE, 2019).
Figure 1- MED Process Flow Diagram (PFD)
Figure 2- Vapour Compression PFD (the reverse osmosis is optional)
Figure 3 – Membrane PFD
Water consumption analysis
To determine the amount of water consumed during each WFI generation process, a mass balance was completed for each system. For simplicity, the mass balance was based on a generation capacity of 17,280 m3/year (2 m3/h).
Water consumption here does not include the WFI generated. It was determined that based on water requirement alone, the VC process utilised the least amount of water, with an annual demand of 8,300 m³/year, as seen in figure 4.
This was followed by the membrane-based process, which required an additional 200 m³/year compared to the VC process. This additional usage was a result of the thermal sanitisation completed daily on the pre-treatment skid for preventing microbial growth.
MED water demand was the highest, with an additional 2,700 m³/year requirement compared to the VC method. As can be seen from figure 5, the steam requirements illustrates that the MED has about 10 times more steam requirements compared to VC whereas there was no steam requirements for the membrane based process for AWFI production (figure 5).
Figure 6 showcases the overall water consumption within the first 20 years of operation (note VC and membrane are reasonably aligned).
Energy consumption analysis
An energy balance was completed for each WFI generation system, taking into account 1) the inlet raw water stream pre-heating requirements; 2) energy consumption of the final treatment (WFI generation stage); 3) the energy required to maintain the product at the required temperature; 4) the energy required during storage; and 5) energy requirements involved in the distribution loop.
The overall energy requirements (1-5) for each process were summated to determine the overall annual energy requirements. The energy consumption for AWFI generation, which can use either VC or membrane processes, the membrane-based process route utilises the least amount of energy for AWFI generation compared to the VC process (reduction of 90%) (Figure 7).
Compared to the MED based technology for HWFI generation, a reduction of 93% was seen for the membrane-based process route (comparing figures 7 and 8). This is due to the additional requirements for the hot storage and the distribution loop for the HWFI processes.
The VC process poses a more viable option for HWFI generation compared to using MED based technology, as evidenced by a 30% reduction of a yearly energy consumption between these two production methods (figure 8).
Sustainability is a key driver in this study, a large CO2 emission reduction can be seen with the implementation of a membrane based AWFI process route rather than the traditionally use of the VC route. Calculations showed that the membrane technology was capable of reducing annual energy usage by 91%.
As the emission intensity of power generation rose by 11.9% to 331 g CO2/ kWh in 2021 (EPA, 2022), the implementation of a membrane based AWFI generation process would be more environmentally impactful compared to HWFI methods.
It was estimated that a reduction of 5% CO2 emissions was possible in the first year of production and by 90% within 20 years of implementation (provided the emission intensity of power generation remained constant).
Similarly for HWFI, the implementation of VC instead of MED resulted in a yearly reduction of 34% of CO2 . Over a 20-year lifespan of utilising VC for HWFI production, about 30% less CO2 would be released into the environment compared to the MED process.
Overall cost analysis
A brief cost review of each WFI generation system was presented in this study. The overall cost of running each WFI generation process was estimated to include the cost of water, energy, equipment, steam and maintenance (in terms of equipment and parts replacement).
This equipment cost for each process included equipment for the purposes of pre-treatment, final treatment, sanitisation, storage and distribution of the WFI. It was found that the annual equipment costs increased in the following order: membrane > VC > MED.
Membrane technology represented an equipment cost reduction of 44% and 35%, when compared to MED and VC based technologies, respectively. Additionally, the equipment costs for ambient storage and distribution was found to be 6.5% lower than that for the HWFI generation.
An additional cash flow analysis was performed for a 30-year lifecycle. Although membrane technology requires frequent replacement to maintain process efficiency, its overall cost remained the lowest when compared to MED and VC process routes. Over 30 years, the membrane-based process cost averaged three-and-a-half times lower than that for the VC method and five times lower compared to the MED approach
From the analysis, it was determined that to produce HWFI, the implementation of the VC process was more optimal in comparison to the MED. It was determined that the VC process reduced water consumption by 2,700 m³/ year, the yearly energy consumption was reduced by 30%, the CO2 production was reduced by 30% per year and finally, the overall cost was reduced by 1.4 times within the first 30 years of production.
For the production of AWFI, the membrane-based process was found to be the most optimal, reducing the yearly energy consumption by 90%, CO2 production was reduced by 34% per year and finally, the overall cost was reduced by five times in the first 30 years of production.
Further research is recommended into the feasibility of generating WFI at an ambient temperature by membrane technology and then storing and distributing to the point of use requiring HWFI to determine if it is more optimal than producing HWFI by VC technology and storing it at hot temperatures.
Author: Magdalena Korneluk, chemical and biopharmaceutical engineering, Munster Technology University. Academic supervisor: Dr Caroline O’ Sullivan, Munster Technology University; industrial supervisor: Treasa Rohrer, PM Group.
1) EPA (2022). EPA data shows Ireland’s 2021 Greenhouse Gas Emissions above pre-Covid levels. Available at https://www.epa.ie/news-releases/news-releases-2022/epa-data-shows-irelands-2021-greenhouse-gas-emissions-above-pre-covid-levels.php#:~:text=This%20resulted%20in%20an%20increase,g%20CO2%2FkWh%20in%202020. [Accessed 23 November 2022]
2) ISPE (2019). ISPE Baseline Guide: Water and Steam Systems. 3rd ed. Academia. [Accessed September 12, 2022.]